The Parenteral Drug Association (PDA) has answered a call by officials at FDA’s Center for Drug Evaluation and Research (CDER) to help define quality metrics that can be used by the agency for its new drug quality enforcement initiative. In a February 2013 Federal Register announcement, FDA explained how it intended to implement Sec. 1003 of the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 (1). Section 1003 requires FDA to form a task force to develop and implement a strategic plan for enhancing its response to preventing and mitigating drug shortages.

As part of this strategy, FDA explained its intention to address the major underlying causes of drug and biological product shortages, which over the past several years have largely resulted from quality-related manufacturing shutdowns. FDA, therefore, is seeking new ideas to encourage high-quality manufacturing and to facilitate expansion of manufacturing capacity. To help with the former, FDA requested input on how drug comanies utilize manufacturing quality metrics.

In response to that Federal Register announcement, PDA formed an 11-member volunteer task force. This group issued comments to FDA on March 13, 2013 that included a discussion of 15 quality metrics commonly used by manufacturers, as well as answers to other questions posed in the announcement (2).

Most importantly, the comments team informed FDA that it would be willing to facilitate dialogue between the agency and industry on the subject of manufacturing and product quality metrics. Over the next several months, the PDA Pharmaceutical Quality Metrics Committee worked with CDER officials to develop an interactive conference and to summarize the dialogue in a Points to Consider (PtC) document.

PDA conference on metricsOn Dec. 9-10, 2013, more than 300 industry experts on drug product quality and manufacturing representing 150 companies participated in PDA’s Pharmaceutical Quality Metrics Conference in Bethesda, Md. The attendees represented a wide range of functional responsibilities including quality, engineering, manufacturing, technical services, and regulatory affairs. Overseas, and domestic, generic-drug, over-the-counter (OTC), CMO, pharmaceutical, and biotech companies that manufacture large and small molecule APIs and drug products were represented. This showing of support for the FDA initiative was well received by CDER Director Janet Woodcock, who took the podium in the closing session to thank PDA and discuss the need to press forward with the metrics initiative.

“This is really important,” Woodcock said. “We are having an ongoing dialogue about this issue of metrics. I was able to come and listen to the report-out from the polls and breakout sessions. I was very intrigued by both the engagement and what people actually said about what is going on. It gave me a lot of hope that we can really make this happen.”

Feedback gained during the interactive workshop, which afforded attendees the opportunity to vote on metrics categories they deemed useful and suggest metrics not presented in advance by the PDA Pharmaceutical Quality Metrics Committee, assisted in the completion of the PtC document, which PDA submitted to FDA on Dec. 19, 2013 (3).

In closing the conference, PDA President Richard Johnson assured participants that the feedback received greatly helped the committee refine the PtC. “Whatever the team was thinking before the meeting, I can assure you it is different today,” he said. “If it was easy, we wouldn’t need a meeting.”

Points to consider
The PtC expresses PDA’s overall support of FDA’s effort to use quality metrics as important tools:

PDA recognizes FDA’s intent is to establish metrics with clinical relevance to patients, which will also move towards a more proactive quality assessment model for companies. PDA also understands the objective is to move organizations from assessing primarily against compliance standards to assessment based on quality performance against established clinically-relevant specifications and driving continual improvement.

Drawing from the discussions at the metrics workshop, the committee outlined many important factors that “must be balanced” for FDA to achieve its objectives, for instance, identifying and defining “leading metrics” (harder to define, but more useful) versus “lagging metrics” (more comonly used today). The committee envisions a time in the future when industry would more widely adopt leading indicators, demonstrating a commitment to the ICH Q10 principle of continuous improvement. Use of leading indicators “is necessary to improve prediction and mitigation of potential drug shortages especially in increasingly complex manufacturing process and supply chain environments,” the committee wrote.

In the PtC document, the committee outlines recommended metrics for FDA collection, broken down as trend metrics per product and trend metrics per site. The former includes confirmed product quality complaint rate by product and batch reject rate by product and the latter includes confirmed out-of-specification (OOS) rate (drug substance and drug product) by site.

The document also highlights useful site and product-specific metrics identified at the conference as “important, but difficult to compare.” Process capability and corrective action and preventive action (CAPA) effectiveness rate are examples.

The PtC includes advice on comparing metrics. Data trends of metrics are “more reliable predictors of potential risk than single values,” the team wrote. The team provided examples to support their claim.

The document also includes a section on “direct comparison metrics” in acknowledgement of FDA’s request for absolute value and trends of metrics appropriate for direct comparison between products and manufacturing sites. If the agency takes that approach, the team recommends limiting it to two product metrics and one site metric reported annually.

In the conclusion, the team warns against “just comparing numbers in order to achieve FDA’s goal of objective measures of product quality, site operations quality, and site systems performance.” The conclusion also warns against unintended consequences of metrics collections.

PDA’s commitment to metrics development
The committee also suggests in the PtC document possible additional activities PDA could pursue in 2014 to help FDA develop the pharmaceutical quality metrics program. They also suggest that FDA could consider offering companies that demonstrate a commitment to quality performance “preferred opportunities,” such as “preferred handling” of post-approval changes to submissions that enhance system/process capabilities and less frequent inspections.

Johnson pledged that PDA “will invite and try to work with other organizations in the coming year to harmonize specifically some definitions of some of these metrics so as we move forward at least that is not a barrier.”